间充质干细胞源性外泌体及其在创面修复中的研究进展
|
摘要
外泌体(exosomes)是细胞分泌的膜性囊泡,其作为干细胞旁分泌因子参与了创面修复。该文对近年间充质干细胞外泌体促进创面修复的研究进展进行综述,外泌体通过调控炎症反应、促进细胞增殖及血管再生、调控细胞外基质重塑及抑制瘢痕形成等多种途径全面地参与了创面修复。工程化干细胞可提高其外泌体功效和产量,为外泌体临床应用带来了巨大的潜力和优势。
Exosomes are membranous vesicles secreted by cells and promote wound healing by paracrine after secretion from stem cells. This article reviews recent advances of wound repair by exsosomes derived from mesenchymal stem cells. By regulating inflammation, promoting fibroblast proliferation and angiogenesis, regulating extracellular matrix remodeling, and inhibiting scar formation, mesenchymal stem cell exosomes can promote wound repair. Furthermore, engineered stem cells can increase their exosomes efficacy and yield, and provide great advantages to the clinical application of exosomes.
Exosomes are membranous vesicles secreted by cells and promote wound healing by paracrine after secretion from stem cells. This article reviews recent advances of wound repair by exsosomes derived from mesenchymal stem cells. By regulating inflammation, promoting fibroblast proliferation and angiogenesis, regulating extracellular matrix remodeling, and inhibiting scar formation, mesenchymal stem cell exosomes can promote wound repair. Furthermore, engineered stem cells can increase their exosomes efficacy and yield, and provide great advantages to the clinical application of exosomes.
引文
[1] Rani S,Ryan AE,Griffin MD,et al.Mesenchymal stem cell-derived extracellular vesicles:toward cell-free therapeutic applications[J].Mol Thera,2015,23(5):812-823.
[2] Katsuda T,Kosaka N,Takeshita F,et al.The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles [J].Proteomics,2013,13(10/11):1637-1653.
[3] Pan BT,Johnstone RM.Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro:selective externalization of the receptor [J].Cell,1983,33(3):967-978.
[4] Johnstone RM,Adam M,Hammond JR,et al.Vesicle formation during reticulocyte maturation.Association of plasma membrane activities with released vesicles (exosomes)[J].J Biol Chem,1987,262(19):9412-9420.
[5] Raposo G,Stoorvogel W.Extracellular vesicles:exosomes,microvesicles,and friends [J].J Cell Biol,2013,200(4):373-383.
[6] Eirin A,Zhu XY,Puranik AS,et al.Integrated transcriptomic and proteomic analysis of the molecular cargo of extracellular vesicles derived from porcine adipose tissue-derived mesenchymal stem cells [J].PLoS One,2017,12(3):e174303.
[7] Phan J,Kumar P,Hao D,et al.Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy [J].J Extracel Ves,2018,7(1):1522236.
[8] Sunkara V,Woo HK,Cho YK.Emerging techniques in the isolation and characterization of extracellular vesicles and their roles in cancer diagnostics and prognostics [J].Analyst,2016,141(2):371-381.
[9] Lotvall J,Hill AF,Hochberg F,et al.Minimal experimental requirements for definition of extracellular vesicles and their functions:a position statement from the International Society for Extracellular Vesicles [J].J Extracell Vesicles,2014,3:26913.
[10] Gardiner C,Ferreira YJ,Dragovic RA,et al.Extracellular vesicle sizing and enumeration by nanoparticle tracking analysis [J].J Extracell Vesicles,2013,2.doi:10.3402/jev.v2i0.19671.eCollection 2013.
[11] Baietti MF,Zhang Z,Mortier E,et al.Syndecan-syntenin-ALIX regulates the biogenesis of exosomes[J].Nat Cell Biol,2012,14(7):677-685.
[12] Wang X,Gu H,Qin D,et al.Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis [J].Sci Rep,2015,5(13721):13721.
[13] Li X,Liu L,Yang J,et al.Exosome derived from human umbilical cord mesenchymal stem cell mediates mir-181c attenuating burninduced excessive inflammation [J].Bio Medicine,2016,8:72-82.
[14] Alexander M,Hu R,Runtsch MC,et al.Exosome-delivered microRNAs modulate the inflammatory response to endotoxin [J].Nat Commun,2015,6:7321.
[15] Zhang B,Wang M,Gong A,et al.HucMSC-exosome mediated Wnt4 signaling is required for cutaneous wound healing [J].Stem Cell,2015,33(7):2158-2168.
[16] Zhang B,Wu X,Zhang X,et al.Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/betacatenin pathway [J].Stem Cell Transl Med,2015,4(5):513-522.
[17] Zhang B,Shi Y,Gong A,et al.HucMSC exosome-delivered 14-3-3ζ orchestrates self-control of the wnt response via modulation of yap during cutaneous regeneration[J].Stem Cells,2016,34(10):2485-2500.
[18] Shabbir A,Cox A,Rodriguez-Menocal L,et al.Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts,and enhance angiogenesis in vitro [J].Stem Cell Dev,2015,24(14):1635-1647.
[19] Hu L,Wang J,Zhou X,et al.Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts[J].Sci Rep,2016,6:32993.
[20] Ding J,Wang X,Chen B,et al.Exosomes derived from human bone marrow mesenchymal stem cells stimulated by deferoxamine accelerate cutaneous wound healing by promoting angiogenesis [J].Biomed Res Int,2019,2019:9742765.
[21] Liang X,Zhang L,Wang S,et al.Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a[J].J Cell Sci,2016,129(11):2182-2189.
[22] Tao SC,Guo SC,Li M,et al.Chitosan wound dressings incorporating exosomes derived from microrna-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model[J].Stem Cell Transl Med,2017,6(3):736-747.
[23] Zhang J,Guan J,Niu X,et al.Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis[J].J Transl Med,2015,13:49.
[24] Li X,Xie X,Lian W,et al.Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model[J].Exp Mol Med,2018,50(4):29.
[25] Bakhtyar N,Jeschke MG,Herer E,et al.Exosomes from acellular Wharton's jelly of the human umbilical cord promotes skin wound healing[J].Stem Cell Res Ther,2018,9(1):193.
[26] 詹小舒,罗冬章,王丙云,等.犬脐带间充质干细胞来源外泌体修复皮肤创伤[J].中国组织工程研究,2018,22(25):4021-4027.
[27] Shi H,Xu X,Zhang B,et al.3,3′-Diindolylmethane stimulates exosomal Wnt11 autocrine signaling in human umbilical cord mesenchymal stem cells to enhance wound healing[J].Theranostics,2017,7(6):1674-1688.
[28] Kim YJ,Yoo SM,Park HH,et al.Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin [J].Biochem Biophys Res Commun,2017,493(2):1102-1108.
[29] 赵彬,吴高峰,张熠杰,等.人羊膜上皮干细胞来源外泌体对大鼠全层皮肤缺损创面愈合的影响[J].中华烧伤杂志,2017,33(1):18-23.
[30] Shi Q,Qian Z,Liu D,et al.GMSC-derived exosomes combined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model[J].Front Physiol,2017,8:904.
[31] Li M,Ke Q,Tao S,et al.Fabrication of hydroxyapatite/chitosan composite hydrogels loaded with exosomes derived from miR-126-3p overexpressed synovial mesenchymal stem cells for diabetic chronic wound healing[J].J Mate Chem B,2016,4(42):6830-6841.
[32] Qazi TH,Mooney DJ,Duda GN,et al.Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs [J].Biomaterials,2017,140:103-114.
[33] Du W,Zhang K,Zhang S,et al.Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer[J].Biomaterials,2017,133:70-81.
[34] Rafiq QA,Coopman K,Nienow AW,et al.Systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem cell yield in bioreactors [J].Biotechnol J,2016,11(4):473-486.
[35] Yan IK,Shukla N,Borrelli DA,et al.Use of a hollow fiber bioreactor to collect extracellular vesicles from cells in culture [J].Meth Mol Biol (Clifton,NJ),2018,1740:35-41.
[2] Katsuda T,Kosaka N,Takeshita F,et al.The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles [J].Proteomics,2013,13(10/11):1637-1653.
[3] Pan BT,Johnstone RM.Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro:selective externalization of the receptor [J].Cell,1983,33(3):967-978.
[4] Johnstone RM,Adam M,Hammond JR,et al.Vesicle formation during reticulocyte maturation.Association of plasma membrane activities with released vesicles (exosomes)[J].J Biol Chem,1987,262(19):9412-9420.
[5] Raposo G,Stoorvogel W.Extracellular vesicles:exosomes,microvesicles,and friends [J].J Cell Biol,2013,200(4):373-383.
[6] Eirin A,Zhu XY,Puranik AS,et al.Integrated transcriptomic and proteomic analysis of the molecular cargo of extracellular vesicles derived from porcine adipose tissue-derived mesenchymal stem cells [J].PLoS One,2017,12(3):e174303.
[7] Phan J,Kumar P,Hao D,et al.Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy [J].J Extracel Ves,2018,7(1):1522236.
[8] Sunkara V,Woo HK,Cho YK.Emerging techniques in the isolation and characterization of extracellular vesicles and their roles in cancer diagnostics and prognostics [J].Analyst,2016,141(2):371-381.
[9] Lotvall J,Hill AF,Hochberg F,et al.Minimal experimental requirements for definition of extracellular vesicles and their functions:a position statement from the International Society for Extracellular Vesicles [J].J Extracell Vesicles,2014,3:26913.
[10] Gardiner C,Ferreira YJ,Dragovic RA,et al.Extracellular vesicle sizing and enumeration by nanoparticle tracking analysis [J].J Extracell Vesicles,2013,2.doi:10.3402/jev.v2i0.19671.eCollection 2013.
[11] Baietti MF,Zhang Z,Mortier E,et al.Syndecan-syntenin-ALIX regulates the biogenesis of exosomes[J].Nat Cell Biol,2012,14(7):677-685.
[12] Wang X,Gu H,Qin D,et al.Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis [J].Sci Rep,2015,5(13721):13721.
[13] Li X,Liu L,Yang J,et al.Exosome derived from human umbilical cord mesenchymal stem cell mediates mir-181c attenuating burninduced excessive inflammation [J].Bio Medicine,2016,8:72-82.
[14] Alexander M,Hu R,Runtsch MC,et al.Exosome-delivered microRNAs modulate the inflammatory response to endotoxin [J].Nat Commun,2015,6:7321.
[15] Zhang B,Wang M,Gong A,et al.HucMSC-exosome mediated Wnt4 signaling is required for cutaneous wound healing [J].Stem Cell,2015,33(7):2158-2168.
[16] Zhang B,Wu X,Zhang X,et al.Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/betacatenin pathway [J].Stem Cell Transl Med,2015,4(5):513-522.
[17] Zhang B,Shi Y,Gong A,et al.HucMSC exosome-delivered 14-3-3ζ orchestrates self-control of the wnt response via modulation of yap during cutaneous regeneration[J].Stem Cells,2016,34(10):2485-2500.
[18] Shabbir A,Cox A,Rodriguez-Menocal L,et al.Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts,and enhance angiogenesis in vitro [J].Stem Cell Dev,2015,24(14):1635-1647.
[19] Hu L,Wang J,Zhou X,et al.Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts[J].Sci Rep,2016,6:32993.
[20] Ding J,Wang X,Chen B,et al.Exosomes derived from human bone marrow mesenchymal stem cells stimulated by deferoxamine accelerate cutaneous wound healing by promoting angiogenesis [J].Biomed Res Int,2019,2019:9742765.
[21] Liang X,Zhang L,Wang S,et al.Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a[J].J Cell Sci,2016,129(11):2182-2189.
[22] Tao SC,Guo SC,Li M,et al.Chitosan wound dressings incorporating exosomes derived from microrna-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model[J].Stem Cell Transl Med,2017,6(3):736-747.
[23] Zhang J,Guan J,Niu X,et al.Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis[J].J Transl Med,2015,13:49.
[24] Li X,Xie X,Lian W,et al.Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model[J].Exp Mol Med,2018,50(4):29.
[25] Bakhtyar N,Jeschke MG,Herer E,et al.Exosomes from acellular Wharton's jelly of the human umbilical cord promotes skin wound healing[J].Stem Cell Res Ther,2018,9(1):193.
[26] 詹小舒,罗冬章,王丙云,等.犬脐带间充质干细胞来源外泌体修复皮肤创伤[J].中国组织工程研究,2018,22(25):4021-4027.
[27] Shi H,Xu X,Zhang B,et al.3,3′-Diindolylmethane stimulates exosomal Wnt11 autocrine signaling in human umbilical cord mesenchymal stem cells to enhance wound healing[J].Theranostics,2017,7(6):1674-1688.
[28] Kim YJ,Yoo SM,Park HH,et al.Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin [J].Biochem Biophys Res Commun,2017,493(2):1102-1108.
[29] 赵彬,吴高峰,张熠杰,等.人羊膜上皮干细胞来源外泌体对大鼠全层皮肤缺损创面愈合的影响[J].中华烧伤杂志,2017,33(1):18-23.
[30] Shi Q,Qian Z,Liu D,et al.GMSC-derived exosomes combined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model[J].Front Physiol,2017,8:904.
[31] Li M,Ke Q,Tao S,et al.Fabrication of hydroxyapatite/chitosan composite hydrogels loaded with exosomes derived from miR-126-3p overexpressed synovial mesenchymal stem cells for diabetic chronic wound healing[J].J Mate Chem B,2016,4(42):6830-6841.
[32] Qazi TH,Mooney DJ,Duda GN,et al.Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs [J].Biomaterials,2017,140:103-114.
[33] Du W,Zhang K,Zhang S,et al.Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer[J].Biomaterials,2017,133:70-81.
[34] Rafiq QA,Coopman K,Nienow AW,et al.Systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem cell yield in bioreactors [J].Biotechnol J,2016,11(4):473-486.
[35] Yan IK,Shukla N,Borrelli DA,et al.Use of a hollow fiber bioreactor to collect extracellular vesicles from cells in culture [J].Meth Mol Biol (Clifton,NJ),2018,1740:35-41.